Therapeutics designed to treat neurodegenerative diseases that affect motor and sensory neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) or chronic pain, have had limited efficacy due to the formidable challenges associated with delivery to the central nervous system (CNS). The inability to cross the blood-spinal cord and blood-brain barrier (BBB) after systemic delivery and insufficient penetration into the parenchyma from the cerebrospinal fluid (CSF) has hampered the use of recombinant neurotrophic factors and proteins. Substantial advances have been recently reported for brain-specific delivery of transcytosing peptide or antibody carriers and brain-targeted exosomes that show promise toward the treatment of brain-afflicting diseases like Alzheimer's disease. Still, few therapeutic options are available for degenerative diseases that affect motor neurons in the spinal cord and of the drugs that have been identified many have been biologics such as proteins, genes and small interfering RNAs that are not readily transported into the nervous system.
Therapeutic molecules can be delivered to the spinal cord by direct injection, remote delivery or intrathecal transplantation of genetically modified cells secreting the molecules of interest. Several engineered viruses that are capable of transducing motor neurons have been used to demonstrate the potential of remote gene transfer in animal models of disease, and ligands for the tetanus toxin receptor have been fused to proteins for delivery to spinal cord neurons, although in general functional protein delivery has not been observed using this strategy.
There remains a need for peptides and related molecules that mediate delivery into the CNS via retrograde transport.